Propranolol inhibits cavernous vascular malformations by β1 adrenergic receptor antagonism in animal models

Li, Wenqing; Shenkar, Robert; Detter, Matthew R; Moore, Thomas; Benavides, Christian R; Lightle, Rhonda; Girard, Romuald; Hobson, Nicholas; Cao, Ying; Li, Yan; Griffin, Erin; Gallione, Carol J.; Zabramski, Joseph M.; Ginsberg, Mark H.; Marchuk, Douglas A.

doi:10.1172/jci144893

Cited by 31 publications

(33 citation statements)

References 26 publications

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“… 54 ). It was recently reported that propranolol ameliorates cavernous malformations in zebrafish by β1-adrenergic antagonism ( 55 ). Further, a central role for Sox18 during zebrafish arteriovenous specification ( 56 , 57 ) and angiogenesis ( 25 ) has been reported, and it is therefore possible that in this model organism, a Sox18-dependent mechanism mediated via propranolol was also at play.…”

Section: Discussionmentioning

confidence: 99%

“…Further, a central role for Sox18 during zebrafish arteriovenous specification ( 56 , 57 ) and angiogenesis ( 25 ) has been reported, and it is therefore possible that in this model organism, a Sox18-dependent mechanism mediated via propranolol was also at play. Oral propranolol reduced lesion burdens in murine models of cerebral cavernous malformation 3, however the effect of the propranolol enantiomers was not investigated in the murine model ( 55 ).…”

Section: Discussionmentioning

confidence: 99%

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Non–beta blocker enantiomers of propranolol and atenolol inhibit vasculogenesis in infantile hemangioma

Seebauer¹,

Graus²,

Huang³

et al. 2022

Journal of Clinical Investigation

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Non–beta blocker enantiomers of propranolol and atenolol inhibit vasculogenesis in infantile hemangioma

Seebauer¹,

Graus²,

Huang³

et al. 2022

Journal of Clinical Investigation

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“…Recent studies have emphasized that chronic models may be more reflective of the course of the human disease (17,(55)(56)(57). We therefore, investigated the expression of VEGF increased in perilesional astrocytes in juvenile Pdcd10 ECKO ;Vegfa tm1.1Nagy mice.…”

Section: Astrocyte-derived Vegf Increases During Ccm Formation In Juvenile Micementioning

confidence: 98%

Astrocytes propel neurovascular dysfunction during cerebral cavernous malformation lesion formation

Lopez-Ramirez¹,

Lai²,

Soliman³

et al. 2021

Journal of Clinical Investigation

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Cerebral cavernous malformations (CCMs) are common neurovascular lesions caused by lossof-function mutations in one of three genes, including KRIT1 (CCM1), CCM2, and PDCD10 (CCM3), and generally regarded as an endothelial cell-autonomous disease. Here we reported that proliferative astrocytes played a critical role in CCM pathogenesis by serving as a major source of VEGF during CCM lesion formation. An increase in astrocyte VEGF synthesis is driven by endothelial nitric oxide (NO) generated as a consequence of KLF2 and KLF4-dependent elevation of eNOS in CCM endothelium. The increased brain endothelial production of NO stabilized HIF-1a in astrocytes, resulting in increased VEGF production and expression of a "hypoxic" program under normoxic conditions. We showed that the upregulation of cyclooxygenase-2 (COX-2), a direct HIF-1a target gene and a known component of the hypoxic program, contributed to the development of CCM lesions because the administration of a COX-2 inhibitor significantly prevented the progression of CCM lesions. Thus, non-cell-autonomous crosstalk between CCM endothelium and astrocytes propels vascular lesion development, and components of the hypoxic program represent potential therapeutic targets for CCMs.

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“…That said, the CVP does lacks CNS accessory cells, such as astrocytes, (Lopez-Ramirez et al, 2021) that that promote CCM development. Indeed, we recently reported that propranolol blocks the embryonic CVP malformation by β1 adrenergic receptor antagonism (Li et al, 2021), a result that comports with the beneficial effects of propranolol in murine CCM models (Li et al, 2021;Oldenburg et al, 2021) and in anecdotal reports in humans (Lanfranconi et al, 2020;Reinhard et al, 2016). We have found that blockade or Rho kinase also ameliorates the CVP lesion (Figure 7-figure supplement 2) as it does murine CCM (McDonald et al, 2012).…”

Section: Ccm2 Crispr Zebrafish Are An Authentic Ccm Modelmentioning

confidence: 53%

Abortive Intussusceptive Angiogenesis Causes Multi-Cavernous Vascular Malformations

Tran

Shaked

et al. 2020

Preprint

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Mosaic inactivation of CCM2 in humans causes cerebral cavernous malformations (CCMs) containing adjacent dilated blood-filled multi-cavernous lesions. We used CRISPR-Cas9 mutagenesis to inactivate zebrafish ccm2 resulting in novel lethal multi-cavernous lesions in the embryonic caudal venous plexus (CVP) caused by obstruction of blood flow by intraluminal pillars. These pillars mimic intussusceptive angiogenesis; however, the pillars failed to fuse to split the pre-existing vessel in two. Abortive intussusceptive angiogenesis stemmed from mosaic inactivation of ccm2 leading to patchy klf2a over-expression and resulting aberrant flow signaling. Surviving adult fish manifested histologically-typical hemorrhagic CCM. Formation of mammalian CCM requires flow-regulated transcription factors, KLF2 and KLF4; fish CCM and the embryonic CVP lesion failed to form in klf2a null fish indicating a common pathogenesis with the mammalian lesion. These studies describe the first zebrafish CCM model and establish a mechanism that can explain the formation of characteristic multi-cavernous lesions.

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Propranolol inhibits cavernous vascular malformations by β1 adrenergic receptor antagonism in animal models

Cited by 31 publications

References 26 publications

Non–beta blocker enantiomers of propranolol and atenolol inhibit vasculogenesis in infantile hemangioma

Non–beta blocker enantiomers of propranolol and atenolol inhibit vasculogenesis in infantile hemangioma

Astrocytes propel neurovascular dysfunction during cerebral cavernous malformation lesion formation

Abortive Intussusceptive Angiogenesis Causes Multi-Cavernous Vascular Malformations

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